This invention relates to the preparation of codeine from morphine and, more particularly, to an improved process for the preparation of codeine which provides for more complete control over the formation of the methylated by-product codeine methyl ether and for a more thorough separation of dimethylaniline and codeine.
Codeine is widely used as an analgesic and is the methyl ether of morphine. While it occurs naturally in opium to a small extent, it has been prepared synthetically by methylation of the phenolic hydroxyl group in morphine. Thus, it is known to prepare codeine by the reaction of morphine with a methylating agent such as dimethyl sulfate or trimethylphenyl ammonium ethoxide or trimethylphenyl ammonium hydroxide in the presence of a base such as aqueous sodium hydroxide, or alcoholic sodium ethoxide. See W. R. Heumann, Bulletin on Narcotics, Vol. 10, No. 3, pp. 15-17 (1958); U.S. Pat. No. 4,764,615 and U.S. Pat. No. 6,204,337. Modified conditions of the process described by Heumann have been used commercially for some years.
Currently employed processes suffer from significant yield loss, great recycle volume, high operator exposure, and extensive cycle times. The yield loss occurs partly from the current need to remove unreacted morphine and color bodies through precipitation, salt crystalilizations, and carbon treatment. Most of the precipitation and crystallization steps require manual digging of a centrifuge or filter. This creates much operator exposure and greater reliance on personal protection equipment. Allergic symptoms from the narcotics can result through extended exposure. Repetitive motion injuries can also occur from the manual digging.
There remains a need for further improvements in the preparation of codeine from morphine in order to more fully control the formation of the undesired by-product codeine methyl ether, and more efficiently provide for the removal of unreacted morphine and for the separation of dimethylaniline from codeine.
Among the several objects of the invention may be mentioned the provision of an improved process for preparing codeine from morphine; the provision of such a process in which formation of the by-product codeine methyl ether is more fully controlled; the provision of such an improved process in which removal of unreacted morphine is more efficiently achieved; and the provision of such an improved process which results in the more efficient production of codeine from morphine and overcomes the significant yield loss, great recycle volume and extensive cycle times of prior art processes. Other objects and features will be in part apparent and in part pointed out hereinafter.
Briefly, the present invention is directed to a process for the preparation of codeine from morphine which comprises the steps of a) reacting morphine with a methylating agent in the presence of a hydrocarbon solvent at a temperature of approximately 100 to 115xc2x0 C. under reflux conditions such that approximately 50% or more of the hydrocarbon solvent is returned to the reaction mixture to substantially avoid the formation of codeine methyl ether; and b) recovering codeine from the reaction mixture. The present invention is also directed to such a process in which step a) above is followed by b) cooling the reaction mixture to approximately 85xc2x0 C. and adding water to terminate the reaction; c) raising the pH of the reaction mixture to approximately 11; d) separating the hydrocarbon solvent phase containing codeine and dimethylaniline from the aqueous phase containing unreacted morphine; and e) adding a dilute mineral or organic acid and approximately 6 to 7 times the volume of water for each volume of hydrocarbon solvent to effect a separation of dimethylaniline and codeine.
In accordance with the present invention, it has now been found that a more efficient process for the production and purification of codeine from morphine may be achieved through certain improved process conditions. In the first step of known processes such as that described in Heumann""s publication for preparing codeine from morphine, a methylating agent such as trimethylphenyl ammonium ethoxide in ethanol is added to a morphine-toluene or other hydrocarbon solvent slurry. At reaction temperatures of 90xc2x0 C. and above, the ethanol and toluene are stripped off. Toluene and ethanol form a binary azeotrope of 32 wt % ethanol which boils at 76.7xc2x0 C. During co-distillation of ethanol and toluene, it has been found in accordance with this invention that with sufficient reflux return, ethanol (b.pt.=78.5xc2x0 C.) and toluene (b.pt.=110.6xc2x0 C.) can be separated returning the bulk of the toluene to the reaction mixture. More particularly, it has been found that when reflux conditions are such that at least 50% or more of the toluene is returned to the reaction mixture, the over concentration of codeine in toluene is avoided thereby preventing the formation of the methylated by-product of codeine, codeine methyl ether. In general, the provision of two theoretical plates in the overhead condenser will insure adequate toluene in the reaction mixture and control the formation of codeine methyl ether.
The methylation reaction is carried out at a temperature of approximately 90xc2x0 to 110xc2x0. Any compatible hydrocarbon solvent such as toluene or xylene may be used as the reaction medium and the methylating agent may be one of those known to those skilled in the art such as trimethylphenyl ammonium chloride, trimethylphenyl ammonium ethoxide, diazomethane or dimethyl sulfate. After the methylation reaction has been carried out for a sufficient time period, usually two to six hours, the reaction mixture is cooled to a temperature of approximately 50xc2x0 to 85xc2x0 C. and water is added to terminate the reaction. Due to the basic nature of the methylating solution, the resulting toluene-water mixture is basic with a pH of approximately 9-10. A small portion of sodium hydroxide or other alkaline material is added to render the mixture more strongly basic with a pH of approximately 11-12. At this pH, unreacted morphine is soluble in water and separation of the water and toluene phases effects a separation of unreacted morphine and codeine.
The toluene phase contains both codeine and dimethylaniline which is left over after the methylating solution of trimethylphenyl ammonium ethoxide has reacted and is neutralized. Dimethylaniline is slightly less basic than codeine and remains in the free base form at a pH of 5.0 to 6.0, while codeine is in the salt form in this pH range. As a salt, codeine is water-soluble and as a free base, the dimethylaniline is soluble in toluene in this pH range. In accordance with the invention, in order to effect a separation of dimethylaniline and codeine, a dilute mineral or organic acid is added to adjust the pH to approximately 4.0 to 6.0 and approximately six to seven times the volume of water for each volume of hydrocarbon solvent is added to effect a separation of dimethylaniline and codeine in the hydrocarbon solvent phase. For this purpose, any dilute mineral or organic acid such as acetic acid, sulfuric acid or hydrochloric acid may be used.
In carrying out the present invention, the morphine starting material may be highly purified or of technical grade and may be in the form of a stable monohydrate containing 5.9% water by weight or even greater levels of water.
In accordance with the invention, the control of codeine methyl ether formation, the removal of unreacted morphine, dimethylaniline and color bodies formed during the methylation reaction advantageously allows for the remaining codeine to be de-colorized via chromatography or other means known to those skilled in the art.